A comprehensive method for quality evaluation of Tibetan medicine Synotis solidaginea by integrating UHPLC-Q-Orbitrap MS chemical profiling and UHPLC-DAD multi-components quantification.

Synotis solidaginea Hand.-Mazz. (SSD) is a commonly used Tibetan medicinal herb with a long history of therapeutic use and has good medicinal value and development and utilization prospects. This study aimed to establish and validate a comprehensive strategy integrating UHPLC-Q Exactive Orbitrap HRMS chemical profiling and UHPLC-DAD multi-components quantification for the holistic quality evaluation of SSD. Using UHPLC-Q Exactive Orbitrap HRMS, a total of 58 components in SSD including flavonoids, organic acids, terpenoids, coumarin, and alkaloids were identified or tentatively characterized by authentic reference standards and accurate masses and characteristic fragment ions. The proportion of flavonoids and organic acids were the most in SSD. Subsequently, 7 characteristic components in SSD were quantified by a newly established UHPLC-DAD method that was validated in terms of linearity and ranges, LOD and LOQ, precision, repeatability, stability, and accuracy. Finally, the method was successfully used for the quality evaluation of 8 batches of SSD collected from 5 production areas in China. ANOVA and post hoc Tukey test are used to evaluate the differences in component content in SSD from different production areas. There are significant differences in the content of SSD from different regions (P < 0.05), which may be related to the climate, altitude, and other natural environments of the regions. This work laid a valuable foundation for further development and comprehensive quality control of SSD.

S-nitrosylation of AMPKγ impairs coronary collateral circulation and disrupts VSMC reprogramming.

Collateral circulation is essential for blood resupply to the ischemic heart, which is dictated by the contractile phenotypic restoration of vascular smooth muscle cells (VSMC). Here we investigate whether S-nitrosylation of AMP-activated protein kinase (AMPK), a key regulator of the VSMC phenotype, impairs collateral circulation. In rats with collateral growth and development, nitroglycerin decreases coronary collateral blood flow (CCBF), inhibits vascular contractile phenotypic restoration, and increases myocardial infarct size, accompanied by reduced AMPK activity in the collateral zone. Nitric oxide (NO) S-nitrosylates human recombinant AMPKγ1 at cysteine 131 and decreases AMP sensitivity of AMPK. In VSMCs, exogenous expression of S-nitrosylation-resistant AMPKγ1 or deficient NO synthase (iNOS) prevents the disruption of VSMC reprogramming. Finally, hyperhomocysteinemia or hyperglycemia increases AMPKγ1 S-nitrosylation, prevents vascular contractile phenotypic restoration, reduces CCBF, and increases the infarct size of the heart in Apoe-/- mice, all of which is rescued in Apoe-/-/iNOSsm-/- mice or Apoe-/- mice with enforced expression of the AMPKγ1-C130A mutant following RI/MI. We conclude that nitrosative stress disrupts coronary collateral circulation during hyperhomocysteinemia or hyperglycemia through AMPK S-nitrosylation.

CD147 Facilitates the Pathogenesis of Psoriasis through Glycolysis and H3K9me3 Modification in Keratinocytes.

Psoriasis is a chronic inflammatory skin disease featuring rapid proliferation of epidermal cells. Although elevated glycolysis flux has been reported in psoriasis, the molecular mechanisms underlying its pathogenesis remain unclear. We investigated the role of the integral membrane protein CD147 in psoriasis pathogenesis, observing its high expression in psoriatic skin lesions of humans and imiquimod (IMQ)-induced mouse models. In mouse models, genomic deletion of epidermal CD147 markedly attenuated IMQ-induced psoriatic inflammation. We found that CD147 interacted with glucose transporter 1 (Glut1). Depletion of CD147 in the epidermis blocked glucose uptake and glycolysis in vitro and in vivo. In CD147-knockout mice and keratinocytes, oxidative phosphorylation was increased in the epidermis, indicating CD147's pivotal role in glycolysis reprogramming during pathogenesis of psoriasis. Using non-targeted and targeted metabolic techniques, we found that epidermal deletion of CD147 significantly increased the production of carnitine and α-ketoglutaric acid (α-KG). Depletion of CD147 also increased transcriptional expression and activity of γ-butyrobetaine hydroxylase (γ-BBD/BBOX1), a crucial molecule for carnitine metabolism, by inhibiting histone trimethylations of H3K9. Our findings demonstrate that CD147 is critical in metabolic reprogramming through the α-KG-H3K9me3-BBOX1 axis in the pathogenesis of psoriasis, indicating that epidermal CD147 is a promising target for psoriasis treatment.

Fast all-fiber ultraviolet photodetector based on an Ag-decorated ZnO micro-pillar.

There are urgent demands of ultraviolet (UV) photodetectors with high sensitivity and fast response due to the wide application of ultraviolet light in the fields of medical treatment, space exploration, optical communication and semiconductor industry. The response speed of traditional ZnO-based UV photodetectors is always limited by the carrier mobility and electrical resistance caused by the external circuits. Utilizing the all-optical detection method may replace the complex circuit structure and effectively improve the response speed of photodetectors. Here, a fast-response fiber-optic UV photodetector is proposed, where a ZnO micro-pillar is fixed on the end face of a fiber-tip and acts as a Fabry-Pérot interferometer (FPI). Under the irradiation of UV light, the photo-generated carriers change the refractive index of the ZnO micro-pillar, leading to a redshift of the interference wavelengths of the ZnO FPI. To enhance this effect, a discontinuous Ag film with an island-like structure is coated on the surface of ZnO micro-pillars through magnetron sputtering, and therefore the sensitivity of the proposed device achieves to 1.13 nm/(W·cm-2), which is 3.9 times higher than that of without Ag-decoration, due to the intensification of photo-carrier change with the help of the Schottky junction formed between Ag film and ZnO micro-pillar. Meanwhile, since the response speed of the proposed device is mainly determined by the temporal RI change of ZnO micro-pillar, the fiber-optic UV photodetector also shows very fast response with a rise time of 35 ns and a decay time of 40 µs. The demonstrated structure takes full advantage of optical fiber devices, exhibiting compactness, flexibility, fast response and immune to electromagnetic interference, which paves a new way for the next generation of photodetection devices.

A Self-Sustaining Antioxidant Strategy for Effective Treatment of Myocardial Infarction.

Myocardial infarction (MI) is the leading cause of death worldwide and can lead to the loss of cardiac function and heart failure. Reactive oxygen species (ROS) play a key role in the pathological progression of MI. The levels and effects of ROS are significantly different in three unique pathological stages of MI, and most antioxidants cannot make corresponding adjustments to eliminate ROS, which leads to a great compromise to treat MI with antioxidants. Herein, an innovative self-sustaining antioxidant strategy is developed to treat MI with self-sustaining selenium-embedded nanoparticles (SSSe NPs). SSSe NPs possess unique self-sustaining antioxidant effects at different pathological stages of MI. This strategy of on-demand ROS elimination during different pathological stages demonstrated excellent MI treatment efficacy and effectively reversed heart failure to normal heart function. The therapeutic mechanism of SSSe NPs is intensively investigated through a series of experiments and mainly involved five critical aspects of myocardial repair: protecting mitochondria, reducing cardiomyocyte apoptosis and ferroptosis, reducing inflammation and fibrosis, and promoting angiogenesis. This strategy not only provides a promising treatment option for MI but also offers inspiration for other ischemic diseases.

A D-Shaped Polymer Optical Fiber Surface Plasmon Resonance Biosensor for Breast Cancer Detection Applications.

Fiber-optic biosensors have garnered significant attention and witnessed rapid development in recent years owing to their remarkable attributes such as high sensitivity, immunity to electromagnetic interference, and real-time monitoring. They have emerged as a potential tool in the realm of biomarker detection for low-concentration and small molecules. In this paper, a portable and cost-effective optical fiber biosensor based on surface plasmon resonance for the early detection of breast cancer is demonstrated. By utilizing the aptamer human epidermal growth factor receptor 2 (HER2) as a specific biomarker for breast cancer, the presence of the HER2 protein can be detected through an antigen-antibody binding technique. The detection method was accomplished by modifying a layer of HER2 aptamer on the flat surface of a gold-coated D-shaped polymer optical fiber (core/cladding diameter 120/490 µm), of which the residual thickness after side-polishing was about 245 µm, the thickness of the coated gold layer was 50 nm, and the initial wavelength in pure water was around 1200 nm. For low-concentration detection of the HER2 protein, the device exhibited a wavelength shift of ~1.37 nm with a concentration of 1 µg/mL (e.g., 5.5 nM), which corresponded to a limit of detection of ~5.28 nM. Notably, the response time of the biosensor was measured to be as fast as 5 s. The proposed biosensor exhibits the potential for early detection of HER2 protein in initial cancer serum and offers a pathway to early prevention of breast cancer.

Prophylactic exercise-derived circulating exosomal miR-125a-5p promotes endogenous revascularization after hindlimb ischemia by targeting endothelin converting enzyme 1.

Background: Prophylactic exercise improves clinical outcomes in patients experiencing severe ischemic diseases. Previous studies have shown that exercise could alter the amount or content of circulating exosomes. However, little is known about the role of precursory exercise-derived circulating exosomes (Exe-Exo) in ischemic diseases. We therefore aimed to explore the function and mechanism of Exe-Exo in endogenous revascularization and perfusion recovery in peripheral arterial disease. Methods and Results: We first determined that 4 weeks of precursory treadmill exercise improved perfusion recovery on days 7, 14 and 21 after unilateral femoral artery ligation (FAL) but had no effect immediately after ligation. Then, local muscle delivery of Exe-Exo promotes arteriogenesis, angiogenesis and perfusion recovery, which could be abolished by GW4869, a well-recognized pharmacological agent inhibiting exosome release. This suggests that Exe-Exo mediated exercise-induced revascularization. In vitro, Exe-Exo enhanced endothelial cell proliferation, migration and tube formation. In addition, we identified miR-125a-5p as a novel exerkine through exosomal miRNA sequencing and RT-qPCR validation. Inhibition of miR-125a-5p abrogated the beneficial effects of Exe-Exo both in vivo and in vitro. Mechanistically, these exercise-afforded benefits were attributed to the exosomal miR-125a-5p downregulation of ECE1 expression and the subsequent activation of the AKT/eNOS downstream signaling pathway. Specifically, skeletal muscle may be a major tissue source of exercise-induced exosomal miR-125a-5p via fluorescence in situ hybridization. Conclusions: Endogenous circulating exosomal miR-125a-5p promotes exercise-induced revascularization via targeting ECE1 and activating AKT/eNOS downstream signaling pathway. Identify exosomal miR-125a-5p as a novel exerkine, and highlight its potential therapeutic role in the prevention and treatment of peripheral arterial disease.

Conditioned medium from the bone marrow mesenchymal stem cells modulates immune response via signal transduction and activator of transcription 6 signaling pathway in an allergic rhinitis mouse model.

BACKGROUND: Allergic rhinitis (AR) is a common immune disease of the nasal mucosa characterized with immunoglobulin E (IgE)-mediated allergic inflammation after exposure to allergens in susceptible population. Previous reports have demonstrated that the bone marrow mesenchymal stem cells (BMSCs) could reduce allergic inflammation. However, there is little knowledge about whether the culture supernatant of BMSCs (conditioned medium, CM) has similar anti- inflammatory potential in treating AR. OBJECTIVE: The study aimed to evaluate the immunoregulatory effects of conditioned medium derived from BMSCs (BMSC-CM) on allergic inflammation in an AR mouse model. MATERIAL AND METHODS: The AR murine model was induced by repeated sensitization and challenges with ovalbumin (OVA). Subsequently the allergic symptoms of AR mice, cytokine levels, the histopathological features of the nasal mucosa and T helper 1 (Th1) : T helper 2 (Th2) cells ratio were evaluated. RESULTS: Treatment with BMSC-CM was found as effective as BMSCs in reducing allergic symptoms and inhibiting eosinophilic infiltration in the nasal mucosa. After BMSC-CM or BMSCs administration, the OVA-specific IgE and interleukin 4 levels in serum decreased and interferon gamma level increased compared with AR mice treated with uncultured fresh medium. Flow cytometry analysis revealed a decrease in Th1:Th2 cells ratio after OVA-sensitization and the ratio was reversed by BMSC-CM and BMSCs treatments. Furthermore, the data revealed that BMSC-CM suppressed the production of signal transduction and activator of transcription 6 (STAT6) at messenger RNA and protein levels in the nasal mucosa. CONCLUSION: BMSC-CM could ameliorate allergic inflammation and regulate the balance of Th cells, and the underlying mechanism was closely related to STAT6 signaling pathway. The immunoregulatory effects of BMSCs could be achieved through paracrine function, and nasal dripping of BMSC-CM might be a novel approach for the treatment of AR.

Chemical analysis of Chrysosplenium from different species by UPLC-Q exactive orbitrap HRMS and HPLC-DAD.

Chrysosplenium is the main component of a variety of Tibetan prescription preparations. Nevertheless, there are few chemical reports for different species of Chrysosplenium, which should be further explored. To this end, ultra-performance liquid chromatography-quadrupole/electrostatic field orbitrap high resolution mass spectrometry (UPLC-Q Exactive Orbitrap HRMS) and high-performance liquid chromatography-diode array detection (HPLC-DAD) were first integrated to qualitatively analyse the chemical characteristics of Chrysosplenium nudicaule, Chrysosplenium carnosum, Chrysosplenium sikangense, Chrysosplenium griffithii, Chrysosplenium absconditicapsulum, Chrysosplenium forrestii and Chrysosplenium axillare. As a result, a total of 40 compounds were identified or tentatively identified from these 7 species of Chrysosplenium, including 21 flavonoids, 3 triterpenoids and a variety of alkaloids, organic acids and anthraquinones, etc. Among them, 6 compounds were detected for the first time, and 8 compounds are common components in all 7 species of Chrysosplenium. In the specific chromatogram, 4 characteristic peaks, namely Riboflavin, 5,4'-dihydroxy-3,6,3'-trimethoxyflavin-7-O-ß-D-glucoside, 5,7,3'-trihydroxy-6,4',5'-trimethoxyflavone and Chrysosplenetin, were selected to evaluate the similarities of 17 batches of Chrysosplenium samples, which ranged from 0.770 to 0.994. The established method is simple, feasible and accurate, and was proven to be suitable for characterizing the chemical compositions of Chrysosplenium from different species and evaluating their similarities by specific chromatogram analysis to clarify the rationality of using Chrysosplenium from different species in clinical medication, which provides experimental data for further quality evaluation of Chrysosplenium.

Que Zui tea ameliorates hepatic lipid accumulation and oxidative stress in high fat diet induced nonalcoholic fatty liver disease.

In this study, the protective effects of hot water (QW) and aqueous-ethanol extracts (QA) from Que Zui tea on non-alcoholic fatty liver disease (NAFLD) were investigated. Quantitative and qualitative analysis revealed that QW and QA were rich in polyphenols, especially 6'-O-caffeoylarbutin. Both QW and QA significantly reduced body weight and liver index, increased serum levels of high density lipoprotein cholesterol (HDL-C), and decreased the levels of total cholesterol (TC), triglyceride (TG), nonesterified free fatty acids (NEFA) and low density lipoprotein cholesterol (LDL-C) in NAFLD rats induced high fat diet. Furthermore, the contents of TC, TG, NEFA, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the liver tissues were inhibited after QW and QA administration. Histopathological examination showed that QW and QA significantly reduced liver lipid accumulation of NAFLD rats. In addition, QW and QA could enhance increase the activity of antioxidant (glutathione, superoxide dismutase and catalase) in the liver by regulation Nrf2 signaling pathway, thereby alleviating liver damage caused by lipid peroxidation. QW and QA activated AMPK/PPAR-α signaling pathway by increasing the expression of adiponectin and its receptor AdipoR2, thereby reducing fat production and enhancing fatty acid ß oxidation. These data suggested that QW and QA had the potential to in the prevention and treatment of NAFLD.

Compact Surface Plasmon Resonance IgG Sensor Based on H-Shaped Optical Fiber.

A compact surface plasmon resonance sensor based on an H-shaped optical fiber is proposed and demonstrated. The H-shaped optical fiber was fabricated experimentally by using hydrofluoric acid to controllably corrode the polarization-maintaining fiber. A satisfactory distance between the outer surface of the fiber and the core can be achieved, and then the surface plasmon resonance effect can be excited by coating a metal film of appropriate thickness on the surface of the fiber. This technology can realize the preparation of multiple samples at one time, compared to the traditional side-polishing technique. The H-shaped optical fiber obtained from corrosion exhibits a high surface quality and short lengths, down to only a few hundred microns. The effects of the proposed H-shaped optical fiber on spectral properties are induced by process parameters, including fiber remaining thickness, coating thickness and fiber length, and were investigated in detail. The prepared sensor was used for the specific detection of human IgG, and the minimum human IgG concentration that the sensor can distinguish is 3.4 µg/mL. Such a compact surface plasmon resonance fiber sensor has the advantages of an easy fabrication, good consistency and low cost, and is expected to be applied in the specific detection of biomarkers.

A comprehensive gene expression profile of allergic rhinitis-derived nasal fibroblasts and the potential mechanism for its phenotype.

BACKGROUND: Allergic rhinitis (AR) is a common immunoglobulin E-mediated immune response involved various cell types, while the role of nasal fibroblasts (NFs) in the pathogenesis of AR is less understood. PURPOSE: The study aimed to uncover the gene expression profile of AR-derived NFs and the potential mechanism for the changed phenotype of AR-NFs. RESEARCH DESIGN: The primary NFs were isolated from 3 AR patients (AR-NFs) and 3 controls (Ctrl-NFs), and the proliferation, migration and interleukins production abilities of NFs were detected respectively. RNA-sequence was used to identify differentially expressed genes (DEGs) in AR-NFs. Transcription factor (TF) regulatory network and bioinformatic analyses were both conducted to clarify the biological roles of DEGs including the TFs. The DEG with the highest validated |fold change (FC)| value, detected by qPCR, was selected for further confirmation. RESULTS: AR-NFs showed a higher proliferation and migration abilities as well as released higher levels of IL-33 and IL-6, compared to Ctrl-NFs. A total of 729 DEGs were screened out in AR-NFs. TF regulatory network indicated that BARX homeobox 1 (BARX1) and forkhead box L1 were the major node TFs. Bioinformatic analyses showed that a large number of DEGs including several target genes of BARX1 were both enriched cytokine-related GO terms, and immune- or inflammation-related pathways. BARX1 had the highest |FC| value, and silencing BARX1 in AR-NFs resulted in the significant downregulation of proliferation and migration abilities, and the production of interleukins. CONCLUSIONS: Our study for the first time provided the gene expression profile of AR-derived NFs, and BARX1 could be developed as a potent target to alleviate the pathogenesis of AR.

Epithelial-Myoepithelial Carcinoma of the Submandibular Gland: Case Report.

Epithelial-myoepithelial carcinoma (EMC) is a rare malignant salivary gland tumor that occurs mostly in the parotid gland. We report a case of EMC of the submandibular gland in a young man. The patient was aware of a slow-growing mass in the right submandibular gland for 1 year. Clinical examination and ultrasound confirmed a right submandibular mass, 2.5 × 3 cm2 in size. Ultrasound-guided fine-needle aspiration indicated a diagnosis of pleomorphic adenoma, which was also suggested by magnetic resonance imaging. The submandibular gland tumor was excised. Immunohistochemical analysis showed carcinoma ex pleomorphic adenoma with a major epithelial-myoepithelial component. The patient was not treated with radiotherapy after surgery. No recurrence was observed during 24 months of follow-up. Because the morphology of EMC is similar to that of a benign tumor, it is frequently initially misdiagnosed. Surgery is always the most effective diagnostic and therapeutic measure for salivary gland tumors, especially those that grow slowly. Resection with negative margins is the treatment of choice for EMC; use of adjuvant radiotherapy is controversial.

Outcome of Endoscopic Optic Nerve Decompression for Traumatic Optic Neuropathy.

OBJECTIVE: This study aimed to evaluate the outcomes of endoscopic optic nerve decompression (EOND) for adults with traumatic optic neuropathy (TON) and seek factors that might affect surgery outcomes. METHODS: From January 2016 to June 2019, 16 adults diagnosed with TON, who underwent endoscopic trans-ethmosphenoid optic canal decompression, were reviewed. All the patients were treated with steroids before the surgery. The main outcome measure was an improvement in visual acuity (VA) after treatment. RESULTS: Eight (50.0%) patients had residual vision before the surgery, while eight (50.0%) had no light perception. After surgical decompression, partial recovery of VA was achieved in three (18.75%) patients who were operated within 10 days and had residual vision before the surgery. However, no improvement in VA was observed for the remaining patients (81.25%) who were operated more than 10 days after injuries. CONCLUSIONS: EOND is beneficial for TON not responding to steroid therapy and can prevent permanent disability if earlier intervention is done prior to irreversible damage to the nerve. Endoscopic optic nerve surgery can decompress the traumatic and edematous optic nerve with proper exposure of optic canal and orbital apex without any major complications. The operation timing and residual vision are important factors affecting outcomes.

CDKN2B-AS1 promotes the proliferation, clone formation, and invasion of nasopharyngeal carcinoma cells by regulating miR-98-5p/E2F2 axis.

OBJECTIVE: To explore the effect of CDKN2B antisense RNA 1 (CDKN2B-AS1) on the proliferation, clone formation, and invasion of nasopharyngeal carcinoma (NPC) cells by regulating miR-98-5p/E2F transcription factor 2 (E2F2) axis. METHODS: The expressions of CDKN2B-AS1, miR-98-5p, and E2F2 in NPC tissues and cell lines (SUNE-1, 5-8F, 6-10B, and HK-1) as well as in peritumoral normal tissues and cell line NP69 were determined by qRT-PCR. Subcellular localization of CDKN2B-AS1 was detected using the fluorescence in situ hybridization assay. The targeting relationships between CDKN2B-AS1 and miR-98-5p as well as between miR-98-5p and E2F2 were analyzed by the dual-luciferase reporter assay and RNA binding protein immunoprecipitation assay. The proliferation, clone formation and invasion of 5-8F cells were measured using the CCK-8 assay, Clone formation assay, and transwell assay, respectively. RESULTS: CDKN2B-AS1 was highly expressed in NPC tissues and cells, whereas the expression of miR-98-5p decreased in the NPC tissues and cells. Silencing of CDKN2B-AS1 inhibited the proliferation, clone formation, and invasion of NPC cells (all P<0.05). CDKN2B-AS1 acted asceRNA of miR-98-5p, and miR-98-5p inhibitor could partially reverse the inhibitory effect of silencing CDKN2B-AS1 on NPC cells (all P<0.05). CDKN2B-AS1 upregulated E2F2 by inhibiting miR-98-5p, and the upregulation of E2F2 partially reversed the inhibitory effect of miR-98-5p overexpression on the NPC cells (all P<0.05). CONCLUSION: CDKN2B-AS1, as a lncRNA, can regulate E2F2 by sponging miR-98-5p to promote the proliferation, clone formation, and invasion of NPC cells.

Corrigendum to "The Clinical and Radiological Characteristics of Inflammatory Myofibroblastic Tumor Occurring at Unusual Sites.

[This corrects the article DOI: 10.1155/2018/5679634.].

AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate.

Hypercholesterolemia, the driving force of atherosclerosis, accelerates the expansion and mobilization of hematopoietic stem and progenitor cells (HSPCs). The molecular determinants connecting hypercholesterolemia with hematopoiesis are unclear. Here, we report that a somite-derived prohematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which in turn transactivates Notch and promotes HSPC emergence. Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch up-regulation are associated with HSPC expansion in hypercholesterolemic human subjects. Genome-wide chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing (RNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) indicate that Srebp2 transregulates Notch pathway genes required for hematopoiesis. Our studies outline an AIBP-regulated Srebp2-dependent paradigm for HSPC emergence in development and HPSC expansion in atherosclerotic cardiovascular disease.

Secretome from bone marrow mesenchymal stem cells: A promising, cell-free therapy for allergic rhinitis.

Allergic rhinitis (AR), characterized by the symptoms of sneezing, rhinorrhea, itchiness and nasal blockage, is a type I allergic disease of nasal mucosa, which is mainly mediated by IgE after exposure to allergens. At present, general drug therapy is limited to alleviating allergic symptoms but fails to regulate the allergic reaction; the recurrence of symptoms and the side effects of the drugs make many patients with AR resist treatments and bring serious impacts on the quality of life. Bone marrow mesenchymal stem cells (BMSCs) are a population of adult stem cells with multipotential differentiation capability, low immunogenicity, and immunoregulatory effects. The unique immunoregulatory properties of BMSCs make them hold great promise in the treatment of chronic inflammation and immune disorders through a paracrine mechanism of anti-inflammatory and anti-allergic effects. The stem cell secretome is defined as the set of molecules secreted to the extracellular space. The secretome such as conditioned media (CM) obtained from BMSCs contains various bioactive molecules and vesicular elements, which may act as therapeutic mediators to support their immunoregulatory effects. Therefore, we hypothesize that the BMSCs secretome may represent a promising treatment for AR by anti-allergic effects via the paracrine mechanism.

The Clinical and Radiological Characteristics of Inflammatory Myofibroblastic Tumor Occurring at Unusual Sites.

Inflammatory myofibroblastic tumor (IMT) can occur rarely in the soft tissue or joint of the limb. We retrospectively collected IMT cases of these rare sites and analyzed their clinical and imaging appearance. Thirteen cases of IMT were clinically diagnosed and underwent surgical procedures, pathological analyses, and postsurgical follow-up in our two hospitals. Other than one case of IMT of the bladder wall that presented with gross hematuria, none presented with local swelling, fever, or weakness. All the cases of IMT occurring at the bone showed destruction and parosteal soft tissue masses. The boundaries between the mass and normal bone were vague, without calcifications or any periosteal reaction. Five cases of IMF showed continuous enhancement on CT; seven cases demonstrated iso- or hyposignal intensity on T1WI; one case showed hypersignal intensity on T1WI, and eight cases demonstrated a hypersignal intensity signal on T2WI. All the masses located in soft tissues showed clear and sharp boundaries with different sizes of the swelling regions surrounding muscle interspaces. Three cases showed homogeneous enhancement, one case demonstrated heterogeneous enhancement, and two cases showed edge enhancement on enhanced MRI scans. On pathology, all the lesions showed an absence of a pseudocapsule, and four cases of ALK were positive. The radiological manifestations of IMT located at the soft tissue and bones were similar to benign tumors in shape; however, peritumoral edema, parosteal soft tissue, and the invasive rim of IMT are similar to the features of malignant tumors. Different radiological methods should be used to obtain an accurate diagnosis.

Induction of microRNA-199 by Nitric Oxide in Endothelial Cells Is Required for Nitrovasodilator Resistance via Targeting of Prostaglandin I2 Synthase.

BACKGROUND: Nitrates are widely used to treat coronary artery disease, but their therapeutic value is compromised by nitrate tolerance, because of the dysfunction of prostaglandin I2 synthase (PTGIS). MicroRNAs repress target gene expression and are recognized as important epigenetic regulators of endothelial function. The aim of this study was to determine whether nitrates induce nitrovasodilator resistance via microRNA-dependent repression of PTGIS gene expression. METHODS: Nitrovasodilator resistance was induced by nitroglycerin (100 mg·kg-1·d-1, 3 days) infusion in Apoe-/- mice. The responses of aortic arteries to nitric oxide donors were assessed in an organ chamber. The expression levels of microRNA-199 (miR-199)a/b were assayed by quantitative reverse transcription polymerase chain reaction or fluorescent in situ hybridization. RESULTS: In cultured human umbilical vein endothelial cells, nitric oxide donors induced miR-199a/b endogenous expression and downregulated PTGIS gene expression, both of which were reversed by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt or silence of serum response factor. Evidence from computational and luciferase reporter gene analyses indicates that the seed sequence of 976 to 982 in the 3'-untranslated region of PTGIS mRNA is a target of miR-199a/b. Gain functions of miR-199a/b resulting from chemical mimics or adenovirus-mediated overexpression increased PTGIS mRNA degradation in HEK293 cells and human umbilical vein endothelial cells. Furthermore, nitroglycerin-decreased PTGIS gene expression was prevented by miR-199a/b antagomirs or was mirrored by the enforced expression of miR-199a/b in human umbilical vein endothelial cells. In Apoe-/- mice, nitroglycerin induced the ectopic expression of miR-199a/b in the carotid arterial endothelium, decreased PTGIS gene expression, and instigated nitrovasodilator resistance, all of which were abrogated by miR-199a/b antagomirs or LNA-anti-miR-199. It is important that the effects of miR-199a/b inhibitions were abolished by adenovirus-mediated PTGIS deficiency. Moreover, the enforced expression of miR-199a/b in vivo repressed PTGIS gene expression and impaired the responses of aortic arteries to nitroglycerin/sodium nitroprusside/acetylcholine/cinaciguat/riociguat, whereas the exogenous expression of the PTGIS gene prevented nitrovasodilator resistance in Apoe-/- mice subjected to nitroglycerin infusion or miR-199a/b overexpression. Finally, indomethacin, iloprost, and SQ29548 improved vasorelaxation in nitroglycerin-infused Apoe-/- mice, whereas U51605 induced nitrovasodilator resistance. In humans, the increased expressions of miR-199a/b were closely associated with nitrate tolerance. CONCLUSIONS: Nitric oxide-induced ectopic expression of miR-199a/b in endothelial cells is required for nitrovasodilator resistance via the repression of PTGIS gene expression. Clinically, miR-199a/b is a novel target for the treatment of nitrate tolerance.